Diazepam (1-methyl-5-phenyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one), a pharmaceutical agent among a class of compounds known as benzodiazepines, is an effective anticonvulsant in the emergency treatment of epileptic seizures. Most typically, diazepam is intravenously administered in a clinical setting at a dose of 5 to 10 mg. Alternatively, diazepam can also be rectally administered (e.g., using Diastat®, Valeant Pharmaceuticals), which may be advantageous for home administration. However, as seizures are generally unpredictable in occurrence, there is a continuous need for simple administration of diazepam that does not require a trained caregiver or a socially awkward route. For example, an atomized delivery of liquid medication to the nasal mucosa (intranasal) may offer a more convenient and effective means of delivery, with the added benefit of rapid onset of action.
An intranasal (IN) dose of 10 to 15 mg diazepam is in most instances appropriate to calm a normal adult suffering from an epileptic seizure. The maximum liquid volume that can be delivered as an atomized nasal spray is about 150 μl per nostril. If one actuation per nostril can be administered, this provides a total volume of 300 μl in which an effective dose could be delivered. The problem, however, with conventional intranasal delivery is the relatively poor solubility of diazepam in aqueous systems (e.g., less than 1 mg/ml in water) that would commonly be used for intranasal delivery. An additional problem of intranasal delivery is that the formulation must be composed of solvents and Solvent that are adequately tolerated, that have a recognized safety profile for use in human, and can be delivered as an atomized spray.
It is therefore not surprising that various intranasal delivery methods for diazepam failed to produce promising results. For example, Goldberg (U.S. Pat. No. 4,950,664/U.S. RE036744) describes a composition of a benzodiazepine in a pharmaceutically acceptable nasal carrier in which the salts of the benzodiazepine were dissolved in water at very low concentration, or in which dissolved triazolam was present in a PEG (polyethylene glycol) formulation at about 3 mg/ml. Both would require multiple nasal sprays into each nostril to deliver the required 10 mg diazepam to be effective. Even if one would administer multiple sprays, effective dosages would likely not be achieved as excess fluid would drain from the nasal mucosa faster than the diazepam can be absorbed.
Another example is described by Choi (U.S. Pat. No. 7,132,112). Here, a composition of diazepam for intranasal administration was proposed in the management of epileptic seizure. However, Choi's composition contains multiple organic solvents, a detergent, and only a minor fraction of water to achieve relatively moderate diazepam concentrations (e.g., 20 mg/ml). Higher apparent concentrations were achieved by Cloyd et. al. (U.S. Appl. Nos. 2007/0208011 and 2007/0021411), teaching a composition of diazepam in a supersaturated solution of glycofurol for intranasal administration in the management of epileptic seizure. However, since Cloyd's solution is supersaturated, it is physically unstable. Diazepam will precipitate over time at room temperature within hours and will thus present difficulties in atomization and delivery in the desired dosage. Further, glycofurol does not have a recognized safety status by the U.S. Food and Drug Administration for use in pharmaceutical formulations.
Therefore, while various compositions and methods for intranasal delivery of diazepam are known in the art, there is still a need for improved intranasal pharmaceutical agents for treatment and management of epileptic seizure.